This proposal considers the following working model to explain how polyclonal T cell stimulation can promote human SLE. 1) Naturally- occurring environmental agents can trigger in vivo polyclonal T cell activation in all hosts. 2) Such polyclonal T cell activation normally results in polyclonal activation of both helper T cells and downregulatory T cells. 3) The polyclonally activated helper T cells have the capacity to promote activation and differentiation of many (if not all) B cells, including those capable of producing pathogenic autoantibodies. 4) The polyclonally activated downregulatory T cells counterbalance this autoimmunity-promoting response, at least in part, via physical lysis of cells crucial to polyclonal Ig production (including the B cells themselves). 5) The numerically small CD8+56+ T cell subset is the predominant effector of this polyclonal downnregulatory CTL activity. 6) Polyclonal downregulatory CTL activity mediated by CD8+56+ T cells is impaired in SLE, allowing for enhanced survival of the cells crucial to polyclonal Ig production and enhanced opportunity for the relevant B cell to produce pathogenic autoantibodies. 7) The CTL defect is a predisposing factor in SLE pathogenesis. This proposal will focus on 4 specific questions based on this working model. 1) Do normal CD8+56+ T cells potently downregulate polyclonal Ig production, and is such CD8+56+ T cell-mediated downregulation impaired in SLE? 2) How are normal downregulatory CD8+56+ T cells generated, and what are the defects in SLE? 3) How do normal CD8+56+ T cells effect their downregulation, and what is the defect in SLE? 4) Does the SLE defect in CD8+56+ T cells antedate onset of overt clinical disease? The answers to these questions should shed considerable light on fundamental pathogenetic immune disturbances in human SLE.